Is a short course of azithromycin effective in the treatment of mild-moderate pelvic

inflammatory disease?

Annual Research Symposium - Sexual Health

1st October 2009

Dr Gillian Dean

Outline

Background of PID

Difficulties with current treatment options / service provision

Epidemiology / complications / aetiology

Aims

Methodology & study design

Outcome measures

Patient / public involvement

Costs / value for money

Normal cervix

Columnar epithelium susceptible to infection with STIs such as chlamydia, gonorrhoea

Cervix acts as a barrier to ascending infection Protective mucous “plug” Mucopurulent cervicitis

“Complicated” infection

Uncomplicated complicated infection

Organisms ascend to cause inflammation of

the upper genital tract

Exact mechanism poorly understood inflammation & proteolytic enzymes

(secretory IgA) break down barriers

influence mid cycle, menses

Infection of the female genital tract

endometritis

salpingitis

tubo-ovarian abscess

peritonitis

Pelvic inflammatory disease (PID)

Broad spectrum of clinical disease

from asymptomatic/mild to severe

infection requiring hospitalisation

Clinical characteristics

lower abdominal pain, discharge,

abnormal bleeding, dyspareunia

lower abdominal / uterine / adnexal

tenderness, cervical excitation

Symptoms ≠ complications

Sub-clinical PID 60%

Overt PID - mild to moderate 36%

Severe PID 4%

Current treatment / service provision

Difficult to diagnose - high index of clinical suspicion

Managed by several specialties – general practice,

gynaecology, GUM, A&E

Several recommended regimens - all 14 days

Patient related issues

young women

symptoms often resolve within 1 week

side effects

ITT estimate 75-80% will have clinical cure

Epidemiology

Incidence of PID unknown

Estimated to account for 1:60 GP visits by females under 45 (1)

Most under 25 years

Behavioural factors that increase the risk of STIs younger age at first sexual intercourse

non-barrier contraception

multiple sexual partners

frequency of partner change (2)

Mechanical breech

IUD insertion, instrumentation

surgical procedure - TOP, D&C

1. Simms I, Rogers P, Charlett A. Int J STD AIDS. 1999;10:448-51

2. Simms I, Stephenson JM, Mallinson H et al. Sex Transm Infect. 2006;82:452-7

Complications

Inadequately treated PID serious

consequences

Complex interplay between immunological,

bacterial virulence & genetic factors

Tubal scarring 1:10 infertility

1:5 chronic pelvic pain

Following 3 or more episodes ectopic pregnancy in up to 1:5 women

infertility in up to 1 in 2

Complications

Inadequately treated PID serious

consequences

Complex interplay between immunological,

bacterial virulence & genetic factors

Tubal scarring 1:10 infertility

1:5 chronic pelvic pain

Following 3 or more episodes ectopic pregnancy in up to 1:5 women

infertility in up to 1 in 2 (1-4)

1. Weström L, Joesoef R, Reynolds G et al Sex Transm Dis 1992; 19:185-92. 2. Weström L. Venereology. 1995;8:219-22. 33. Adler MW, Belsey EH, O'Connor BH. Br J Vener Dis 1982;58:151-7. 4.4. Buchan H, Vessey M, Goldacre M, Fairweather J. Br J Obstet Gynaecol. 1993;100:558-62

Which infections cause PID?

Caused by organisms ascending from

the cervix / vagina (1)

Chlamydia trachomatis (13-44%)

Neisseria gonorrhoea (14%)

Mycoplasma genitalium (8-16%)

No organism identified (40-70%)

anaerobes (60%)

1. Ness RB, Soper DE, Holley RL, et al, for the PID Evaluation and Clinical Health (PEACH) Study Investigators. Am J Obstet Gynecol 2002; 186:929-937

Mycoplasma genitalium

STI - first described in 1980 - urethritis, cervicitis, PID

Very difficult to culture

More knowledge since development of NAATs (1)

No routine testing available - research tool at present

As common as chlamydia/gonorrhoea in certain groups

Detected in 14-16% of women with PID

Widespread antibiotic resistance - tetracyclines, penicillins, fluoroquinolones

41% of women with positive test given doxycycline remain positive at 30 days

with an increased risk of short-term treatment failure (RR 4.6, 95% CI 1.1-20.1)

trends towards increased long-term complications (2).

Susceptible to macrolides with azithromycin being most active

1. Horner PJ, Gilroy CB, Thomas BJ. Lancet 1993;342:582-5

2. Haggerty CL, Totten PA, Astete SG et al. Sex Transm Infect. 2008; 84:338-42

Azithromycin

t½ 68 h, takes 16-17 days to clear 3 RCTs using varying regimens / doses / comparator

arms (1,2,3)

Comparable / better cure rates c.f. doxycycline Concern that MG may develop antibiotic resistance

using stat doses

Clinical efficacy data urgently required

Expert opinion regarding a 5-day course of azithromycin

Considered pharmacologically / microbiologically effective for the pathogens

involved (personal communication Prof Cathy Ison, Phillip Hay)

1. Bevan CD, Johal BJ, Mumtaz G et al. Br J Obstet Gynaecol 1995; 102:407-4142. Malhotra M, Sharma JB, Batra S et al.. Indian J Med Sci 2003; 57: 549-55 3. Savaris RF, Teixeira LM, Torres TG et al. Obstet Gynecol 2007;110:53-60

Hypothesis

Women taking a shorter course of therapy for mild-moderate PID will have a greater chance of overall clinical success defined by both clinical cure and ability to complete the treatment course

Aims

To compare outcomes in women with mild-moderate PID given:

5-days azithromycin o.d. & metronidazole b.d. with 1 dose of i.m. ceftriaxone

(total 28 tablets)

or

the current standard of care given over 14-days (total 90 tablets)

two approaches recommended in national guidelines:

14-days doxycycline & metronidazole b.d. with 1 dose of i.m. ceftriaxone (Brighton)

or

14-days ofloxacin & metronidazole b.d. (Sheffield)

Research plan

Open label randomised controlled trial

Women diagnosed with mild-moderate PID

Brighton & Sheffield* GUM clinics

Referrals from gynaecology and primary care

*reviewers’ advice to involve further centre - large GUM clinic, able to recruit in timely fashion, with

sufficient research infrastructure

Primary outcome measure

Clinical efficacy of the treatment regimen at day 14-21

Defined as 70% or greater reduction in tenderness score compared with

baseline (visual analogue scale & modified McCormack pain scales)

Any patient requiring treatment switch prior to day 14 for side effects, or

not completing therapy (for any reason) treatment failure

Women not returning for the 14-21 day assessment will not be

evaluable treatment failure

Modified McCormack pain scale

To assess direct & rebound abdominal tenderness in 4

abdominal quadrants

cervical motion tenderness

uterine tenderness

right/left adnexal tenderness

A score is given for these areas where 0= tenderness absent

1= tenderness described by the patient but not manifested by changes in facial expression or muscle tone

2= tenderness resulting in altered facial expression or muscle tone

3= tenderness causing observable, marked distress

The maximum possible score is 36

Secondary outcome measures (1)

Tolerability of medication assessed using a patient questionnaire

and clinician report, defined as:

percentage of women reporting any side effects attributable to treatment

percentage of women discontinuing/ switching medication due to side

effects

Secondary outcome measures (2)

Adherence to medication assessed using

self report, pill count & adherence

monitoring system defined as:

a) percentage completion rate (number of

women completing course of treatment)

b) percentage adherence (percentage of

medication taken by women)

Secondary outcome measures (3)

Estimation of mycoplasma prevalence in the study population

Microbiological cure in women with positive:

chlamydia

gonorrhoea

mycoplasma

Cost of treatment defined as relative costs of different treatment

regimens including any extra costs incurred by needing to alter or

re-start treatment

Secondary outcome measures (4)

Long-term outcomes (subject to separate consent as part of an

independently funded sub-study)

Assessed by contacting GP 5 years after study start

Defined as the percentage of women experiencing:

pregnancy (what proportion are ectopic)

chronic pelvic pain (at least two consecutive consultations with pelvic

pain)

infertility (failure to conceive in the setting of sexual activity without

contraception)

Inclusion / exclusion criteria

Inclusion criteria

Pelvic discomfort for < 30 days

Direct lower abdominal

tenderness +/- rebound

tenderness

Adnexal/ cervical motion

tenderness

Exclusion criteria

Women not consenting

Age < 16 years

Acute abdominal pain requiring hospitaln

Positive pregnancy test

UTI

Absence of cervical pus cells on

microscopy

Temp. >38oC (indicates severe infection)

Antibiotics within the last 7 days

Known allergy to antibiotic component

Ultrasound scan showing other pathology

Enrolment & trial procedure

Baseline - sequential women

STI screen / PT Abdominal / pelvic examination

Research nurse for randomisation / VAS

Explain treatment / adherence monitoring system

Review at 14-21 days

Review at 48-72h if not responding

VAS / side effects Q / pill count / self report / AMS

Reassessed by clinician (blinded)

6 weeks Review for TOC or telephone call

Sample size

Approx 75% of women initiating a 14-day treatment course will experience a positive

outcome (ITT) (1,2,3)

To detect a 15% improvement in response rate in azithromycin arm (response rate:

90%)

N=112 women in each treatment arm (80% power, alpha=5%)

Brighton GUM / gynaecology 200 patients/year

Sheffield GUM 140 patients/year

Anticipate < 30% women will decline to take part (no additional visits, no increase in

pill burden, no increase in side effect profile)

1. Piyadigamage A, Wilson J. Sex Transm Infect 2005; 81: 233-2352. Savaris RF, Teixeira LM, Torres TG et al. Obstet Gynecol 2007;110:53-603. Ross JDC, Cronje HS, Paszkowski T et al. Sex. Transm. Inf 2006; 82: 446-451

Recruitment

Recruitment rates will be assessed monthly

If recruitment falls expected rate

Steering Group will investigate reasons for this

will contact local GP practices directly

“LES for young peoples’ sexual health” practices

invite further referrals via the South East Primary Care Research Network

Economic analysis

Will compare the absolute cost of current standard rx with

new shorter course

Clinic records examined at 3 months from recruitment

Relative cost- effectiveness

information for index episode & all subsequent clinic contacts

treatment for side effects / relapses, diagnostic tests,

medication changes and repeat prescriptions

The costs of drugs, tests & clinic consultations will be

obtained from local financial managers and validated

sources

Public involvement

Pelvic pain support group - posted message

viewed 656 times - no one has joined the discussion

highlights the recognised difficulties of engaging user involvement in

GUM service provision & research

Clinic questionnaire - anonymous questionnaire at PID follow-up

20% had side effects 20 doxycycline

Focus group - YPC, Claude Nicol Centre

confirmed that women found 2-week course difficult to take

all women willing to take part in this study

Lay representative

member of the study Steering Group

has been involved with application

Value for money

If improved treatment completion /cure rate

need for repeat treatments

pressure on GUM clinics

costly long-term complications e.g. ectopic pregnancies

significant cost savings to the NHS

benefit to patients (immediate / future)

influence local & national guidelines

Estimated chlamydia related PID - long-term complications, ectopic

pregnancy & infertility cost the NHS around £50 million a year (1)

Allows the establishment of a cohort in which longer term complications

will be assessed 5 years after study start

1. Adler MW, Belsey EH, O'Connor BH. Morbidity associated with pelvic inflammatory disease. Br J Vener Dis 1982;58:151-7

Research for Patient Benefit

Application in process Submitted 25th September 2009 Decision announced March 2010

Staffing £174,000 Mycoplasma testing £5,800 Adherence monitoring systems / lap-top / etc £15,500 Admin / CRFs / open access publishing / MHRA £4,000 Travel / subsistence £3,700 Other (estates, indirect costs) £47,000

£249,000

Conclusion

First estimate of mycoplasma prevalence in PID in Brighton & Sheffield may lead to implementation of routine clinical testing

Insufficient evidence at present to support use of azithromycin for mild-

moderate PID 5-day course -less tablets, easier to take, better tolerated

better clinical / microbiological outcomes

simplicity more uniform approach across specialities

Potential to influence the management of PID throughout the NHS, improve

the treatment experience & outcomes for patients, & reduce the spread of

STIs